The purpose of this career development award is to obtain support to design and conduct clinical trials that utilize novel, mechanism-based agents while also mentoring fellows and junior faculty in the discipline of early clinical trials research. The overall objective of the clinical and translational research is to develop novel regimens for the treatment of colorectal cancer that target specific biological alterations thereby resulting in strategies that are not only more effective, but also potentially less toxic than current chemotherapy regimens. The Specific Aims of the research proposal are to: 1) Develop preclinical models of mechanism-based therapy for colorectal cancer that targets both tumor and endothelial cells using the dual VEGF-R and EGF-R tyrosine kinase inhibitor, ZD6474, chemotherapy, and celecoxib, 2) Develop novel combinations of targeted agents (without chemotherapy) that impact upon signal transduction and pro-survival factors as potential maintenance regimens in CRC after best response, and 3) Clinically test the regimens developed in Specific Aims 1 and 2 in patients with metastatic CRC, incorporating detailed pharmacological, biological and imaging studies to assess the relationships between drug exposure, biological effect and patient benefit. These Specific Aims reflect the areas of interest and expertise of the Principal Investigator and demonstrate the focus of hypothesis-driven research that would be funded by this proposal. To facilitate the training of physicians in high quality patient-oriented research, the Principal Investigator will continue a training and mentoring program in Developmental Therapeutics which will utilize the above Specific Aims and a focused curriculum as a means to advance the careers of fellows and junior faculty in disease-directed clinical and translational cancer research.